Annals of Oncology 12:389-395, 2001
© 2001 European Society for Medical Oncology
research-article |
Phase I study of the matrix metal loproteinase inhibitor, BAY 12–9566*
1Mayo Clinic Cancer Center Rochester, Minnesota
2Cardiopulmonary/Oncology Clinical Research, BAYER Inc. Pharmaceutical Division West Haven, Connecticut, USA
Correspondence to:C. Erlichman, MD, Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA, E-mail: erlichman.charles{at}mayo.edumayo.edu
Background: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12–9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity.
Patients and methods: BAY 12–9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks.
Results: Thirteen patients were entered on trial. BAY 12–9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7–560). Mean trough levels of BAY 12–9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500–42,000-fold above the K1s for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12–9566 administration.
Conclusions: The recommended dose for further testing is 800 mg p.o. b.i.d.
antimetastatic, gelatinase A, gelatinase B. inhibitor, matrixmetalloproteinase
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